|Year : 2021 | Volume
| Issue : 2 | Page : 389-393
George Abraham1, Alok Shetty1, Pavankumar Biraris2, Anil Tibdewal3, Maheema Bhaskar2, Amit Janu4, Sandeep P Tandon2
1 Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
2 Department of Pulmonary Medicine, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
3 Department of Radiation Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
4 Department of Radiodiagnosis, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
|Date of Submission||11-May-2021|
|Date of Decision||28-May-2021|
|Date of Acceptance||13-Jun-2021|
|Date of Web Publication||30-Jun-2021|
Sandeep P Tandon
Department of Pulmonary Medicine, Tata Memorial Hospital, Parel, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Abraham G, Shetty A, Biraris P, Tibdewal A, Bhaskar M, Janu A, Tandon SP. Patterned abrasions. Cancer Res Stat Treat 2021;4:389-93
| Case Vignette|| |
A 43-year-old male patient with no history of comorbidities or addictions presented to our hospital complaining of cough with mucoid expectoration and gradually progressing breathlessness over the past 3 months. He was initially evaluated at another center with a contrast-enhanced computed tomography (CECT) scan, which revealed an ill-defined hyperdense lesion of size 7 cm × 6 cm × 7 cm in the lower lobe of the right lung, involving the right main bronchus and right pulmonary artery with a right lower paratracheal node.
The patient was further evaluated with fluorodeoxyglucose (FDG)-positron emission tomography and CECT, which also showed an FDG-avid, heterogeneously enhancing soft tissue mass of size 7.4 cm × 7 cm × 7 cm with a maximum standardized uptake value (SUVmax) of 15.69 involving the superior segment of the right lower lobe abutting the pleura, encasing the right main bronchus and the right upper lobar bronchus, and indenting the bronchus intermedius. The mass infiltrated the mediastinum, merging with the subcarinal (station 7) and right hilar nodes (station 10), abutting the right pulmonary trunk, and encasing the descending interlobar pulmonary artery branch. There were a few right lower paratracheal (station 4) and paraesophageal (station 8) nodes, the largest measuring 2 cm × 1.6 cm, with an SUVmax of 10.55. There were no suspicious nodules in the contralateral lung or hilum or distant metastases [Figure 1]a and [Figure 1]b. A CT-guided biopsy of the right lower lobe mass revealed adenocarcinoma histology, with immunohistochemistry suggestive of primary pulmonary origin. Magnetic resonance imaging of the brain was normal with no evidence of metastasis. As per the 8th edition of the American Joint Committee on Cancer manual, the right lower lobe adenocarcinoma was staged as cT4N2M0. Based on the discussion in the multidisciplinary tumor board, the disease was deemed unresectable in view of the radiological multi-station N2 nodal status (3 FDG-avid nodal lesions: lower paratracheal [station 4], subcarinal [station 7], and paraesophageal [station 8]) and encasement of the interlobar pulmonary artery and the right main bronchus. The right lower lobe mass was central in location and contiguous with the mediastinal node; dosimetric planning images [Figure 1]c showed that the primary and nodal diseases could be incorporated in acceptable radiotherapy (RT) field portals. As there was no evidence of distant metastases, treatment with definitive concurrent radical chemoradiation with curative intent was planned. The patient was simulated in a supine position with the arms over the head using the FLAT MEDTECH device for immobilization. No respiratory gating/tracking technique was used. The color dosimetric image for RT planning is shown in [Figure 2]c. The planning tumor volume (PTV) was 625 cm3, with 473 cm3 for the primary tumor and 152 cm3 for the nodal disease. The percentage of normal lung volume receiving ≥20 Gy (V20) was 24% and that receiving ≥35 Gy (V35) was 7.8%. The patient received radical external beam RT to the primary tumor and the nodes at a dose of 60 Gy/30 fractions using image-guided (IG) intensity-modulated radiotherapy on the Truebeam linear accelerator radiotherapy system (Varian-A Siemens Healthineers Company, United States of America) over 6 weeks, with no undue gaps or major immediate toxicities (occurring within 3 months). The patient also received concurrent chemotherapy with etoposide at a dose of 100 mg/m2 on days 1–3 of a 21-day cycle and cisplatin at a dose of 37.5 mg/m2 on days 1 and 8 of each cycle for a total of 2 cycles. He was administered the third cycle of chemotherapy after the completion of RT. While he was due for the fourth cycle, he presented with acute, new-onset cough and fever that had persisted for 5 days. A clinical examination revealed bronchial breathing with crackles over the mammary, right infra-scapular, and infra-axillary regions. Further, CECT imaging of the thorax and abdomen revealed a new-onset patchy consolidation with ground-glass opacities in the entire right lung and a significant interval decrease in the previously observed right lower lobe mass (non-measurable). There was a mild interval decrease in the metastatic nodes in the subcarinal, right hilar, and paratracheal regions, the largest measuring 1.8 cm × 1.5 cm in the paratracheal region (previously measured 2.2 cm × 2.2 cm) [Figure 2]a and [Figure 2]b.
|Figure 1: (a and b) Contrast-enhanced computed tomography images of the thorax with axial sections in the lung window at baseline showing an ill-defined hyperdense lesion of size 7 cm × 6 cm × 7 cm in the right lower lobe of the lung, with a paratracheal node involving the right main bronchus and right pulmonary artery, (c) color dosimetric contrast-enhanced computed tomography images of the thorax with coronal sections showing the radiation planning tumor volumes|
Click here to view
|Figure 2: (a and b) Contrast-enhanced computed tomography images of the thorax with axial sections in lung window at 3 months after the completion of chemoradiation showing a new-onset patchy consolidation with ground glass opacity in the entire right lung with a significant interval decrease compared to the previously seen neoplastic right lung mass (non-measurable), mild interval decrease in the metastatic nodes in the subcarinal, right hilar, and paratracheal regions, with the largest node measuring 1.8 cm × 1.5 cm in the paratracheal region (previously measured 2.2 cm × 2.2 cm), (c) color dosimetric contrast-enhanced computed tomography images of the thorax with axial sections showing the radiation planning tumor volumes|
Click here to view
What is the diagnosis, and what should be done next? Once you have finalized your answer, turn to pg. 390 to read on.
| Work-Up and Clinical Course|| |
The differential diagnoses considered at this point were pneumonia caused by bacterial, viral, or fungal infection and radiation-induced pneumonitis. Complete blood count showed normal white blood cell and neutrophil counts, and serial blood cultures were sterile. The reverse transcription-polymerase chain reaction test for the severe acute respiratory syndrome coronavirus 2 was negative. The patient was started on broad-spectrum antibiotics (cefoperazone-sulbactam, teicoplanin, azithromycin), and bronchoscopy was performed 3 days after the start of antibiotic treatment (day 4 of illness). The bronchoalveolar lavage (BAL) fluid smear and culture were negative for bacteria and fungi and the BAL galactomannan assay also showed negative results. However, the fever persisted without any clinical improvement on antibiotics. In view of the pneumonitis being typically limited to the radiation field, the characteristic sparing of the left lung (non-irradiated field), poor response to antibiotics, and negative infective work-up, the diagnosis of radiation pneumonitis was arrived at. The patient was treated with oral prednisolone at a dose of 1 mg/kg of body weight tapered over 4 weeks, with the improvement of dyspnea and fever and radiological resolution as shown in [Figure 3]a and [Figure 3]b. The patient was subsequently advised surveillance, and consolidation durvalumab was deferred in view of the financial constraints.
|Figure 3: (a and b) Contrast-enhanced computed tomography images of the thorax with axial sections in the lung window at 1 month post initiation of treatment with steroids for radiation-induced pneumonitis showing marked resolution of the ground glass opacities of the right lung with residual consolidation in the right lower lobe suggestive of radiological response to steroids|
Click here to view
| Discussion|| |
Radiation-induced pneumonitis is a common side-effect of thoracic radiotherapy given for various oncological indications. The factors governing the predisposition of patients to radiation pneumonitis include the volume of the irradiated parenchyma, absorbed dose, number of fractions dividing the cumulative absorbed dose, individual doses per fraction, and the radiation dose rate of the output device., In patients with lung cancer, the incidence of radiation pneumonitis reported in the literature ranges from 10% with the use of stereotactic body radiation therapy to 30% with the conventional technique of dose fractionation. A few case reports have also described the occurrence of fatal pneumonitis in some patients. Older age, disease located in the mid-lower lung, presence of comorbidities, concurrent chemotherapy, and larger tumor size have been significantly correlated with higher incidences of pneumonitis of grade 3–5. Chemotherapeutic drugs such as alkylating agents, anthracyclines, taxanes, platinum agents, antimetabolites, epipodophyllotoxins, and even immune checkpoint inhibitors have been shown to potentiate the development of radiation pneumonitis.,
The alveolar-capillary membrane is the functional unit of the lungs which participates in the exchange of gases and is considered to be the most sensitive to ionizing radiation. At a cellular level, cytotoxic damage occurs within minutes of exposure to ionizing radiation in the vascular endothelial cells and type 1 pneumocytes. At a molecular level, the energy from the radiation breaks the chemical bonds, producing reactive oxygen species and reactive nitrogen species, which in turn cause damage to the cellular DNA. This results in immune cell infiltration, increased vascular permeability, and pulmonary edema caused by cytokine and chemokine release leading to reversible radiation pneumonitis.
The clinical manifestations of radiation pneumonitis include cough, breathlessness, low-grade fever, and chest pain. Although these symptoms usually manifest 12–24 weeks after the completion of RT, they may occur sooner in life-threatening cases. The early radiological changes include ground-glass opacities, diffuse haziness, and pleural effusion. The later stages are characterized by alveolar infiltrates and dense consolidation. The untreated sequelae include volume loss, lung fibrotic changes, and pneumothorax. The diagnosis of radiation pneumonitis is based on multiple factors including the typical temporal profile of 12–24 weeks post RT completion, clinical symptoms and signs of pneumonitis localized to the field of irradiation, radiological features in the field of irradiation that are not confined to the normal anatomical lobar boundaries (referred to as the straight-line effect), and laboratory findings suggestive of acute inflammation with no evidence of active infection. Immune-mediated lymphocytic alveolitis can occasionally result in organizing pneumonia outside the irradiated field and rarely manifests as recurrent migratory organizing pneumonitis. Image-based radiation techniques, like IG radiation therapy (IGRT), have decreased the volume of lung irradiated during RT, thereby decreasing the incidence and severity of pneumonitis.
The various grading systems that can be used to assess the severity of radiation pneumonitis are presented in [Table 1].
Patients with minimal or no symptoms of pneumonitis, with >10% reduction on the pulmonary function tests calculated based on the diffusing capacity of the lungs for carbon-monoxide (DLCO) are treated with inhaled high-dose corticosteroids like budesonide. On the other hand, treatment with oral glucocorticoids, such as prednisolone at a dose of 1 mg/kg, forms the backbone of treatment of radiation pneumonitis in symptomatic patients, with a gradual tapering of the dose over 2–3 months. Other immunosuppressive agents that are used in steroid-refractory settings or as steroid-sparing include azathioprine and cyclosporine., Although there is some evidence for the prophylactic use of pentoxifylline and amifostine with concurrent chemoradiation in patients with lung cancer, it is not practiced in the real-world scenario in most of the centers due to the lack of studies measuring tumor control and survival benefit as a result of its greater protective effect on the normal tissues as compared to the tumor tissue. Experiments in murine models suggest a potential role of antifibrotics like pirfenidone in minimizing and treating radiation pneumonitis.
The long-term outcomes of the patients are favorable with early diagnosis and rapid initiation of treatment with immunosuppressive agents like steroids. Almost all the patients have partial to complete recovery of clinical symptoms and radiological disease, along with improvement in the pulmonary function test parameters like DLCO occurring between 3 and 18 months of completion of RT. The advent of consolidation therapy with durvalumab post chemoradiation in patients with non-small-cell lung cancer based on the PACIFIC trial has witnessed an increased recognition and awareness of radiation pneumonitis. About 25% of patients on durvalumab developed symptomatic pneumonitis, with good response to steroids. Durvalumab could be re-challenged in 70% of the patients, with recurrence of pneumonitis in 14% of the patients after re-challenging durvalumab.
| Conclusion|| |
The incidence of radiation pneumonitis is decreasing with modern RT techniques. However, a high clinical suspicion is required for its early diagnosis in case of new-onset or worsening of respiratory symptoms post chemoradiation. Early prompt initiation of immunosuppression is crucial for the clinical and radiological recovery of the patients.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understand that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Vasić L, Durdević P. Radiation-induced lung damage – Etiopathogenesis, clinical features, imaging findings and treatment. Med Pregl 2012;65:319-25.
Giridhar P, Mallick S, Rath GK, Julka PK. Radiation induced lung injury: Prediction, assessment and management. Asian Pac J Cancer Prev 2015;16:2613-7.
Keffer S, Guy CL, Weiss E. Fatal radiation pneumonitis: Literature review and case series. Adv Radiat Oncol 2020;5:238-49.
Vogelius IR, Bentzen SM. A literature-based meta-analysis of clinical risk factors for development of radiation induced pneumonitis. Acta Oncol 2012;51:975-83.
Zhao J, Yorke ED, Li L, Kavanagh BD, Li XA, Das S, et al.
Simple factors associated with radiation-induced lung toxicity after stereotactic body radiation therapy of the thorax: A pooled analysis of 88 studies. Int J Radiat Oncol Biol Phys 2016;95:1357-66.
Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, et al.
PROCLAIM: Randomized Phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol 2016;34:953-62.
Shaverdian N, Thor M, Shepherd AF, Offin MD, Jackson A, Wu AJ, et al.
Radiation pneumonitis in lung cancer patients treated with chemoradiation plus durvalumab. Cancer Med 2020;9:4622-31.
Ullah T, Patel H, Pena GM, Shah R, Fein AM. A contemporary review of radiation pneumonitis. Curr Opin Pulm Med 2020;26:321-5.
Hanania AN, Mainwaring W, Ghebre YT, Hanania NA, Ludwig M. Radiation-induced lung injury: Assessment and management. Chest 2019;156:150-62.
Rovirosa A, Valduvieco I. Radiation pneumonitis. Clin Pulm Med 2010;17:218.
Monson JM, Stark P, Reilly JJ, Sugarbaker DJ, Strauss GM, Swanson SJ, et al.
Clinical radiation pneumonitis and radiographic changes after thoracic radiation therapy for lung carcinoma. Cancer 1998;82:842-50.
Bledsoe TJ, Nath SK, Decker RH. Radiation pneumonitis. Clin Chest Med 2017;38:201-8.
Sterzing F, Engenhart-Cabillic R, Flentje M, Debus J. Image-guided radiotherapy: A new dimension in radiation oncology. Dtsch Arztebl Int 2011;108:274-80.
Arroyo-Hernández M, Maldonado F, Lozano-Ruiz F, Muñoz-Montaño W, Nuñez-Baez M, Arrieta O. Radiation-induced lung injury: Current evidence. BMC Pulm Med 2021;21:9.
Henkenberens C, Janssen S, Lavae-Mokhtari M, Leni K, Meyer A, Christiansen H, et al.
Inhalative steroids as an individual treatment in symptomatic lung cancer patients with radiation pneumonitis grade II after radiotherapy – A single-centre experience. Radiat Oncol 2016;11:12.
McCarty MJ, Lillis P, Vukelja SJ. Azathioprine as a steroid-sparing agent in radiation pneumonitis. Chest 1996;109:1397-400.
Giuranno L, Ient J, De Ruysscher D, Vooijs MA. Radiation-induced lung injury (RILI). Front Oncol 2019;9:877.
Antonadou D. Radiotherapy or chemotherapy followed by radiotherapy with or without amifostine in locally advanced lung cancer. Semin Radiat Oncol 2002;12:50-8.
Qin W, Liu B, Yi M, Li L, Tang Y, Wu B, et al.
Antifibrotic agent pirfenidone protects against development of radiation-induced pulmonary fibrosis in a murine model. Radiat Res 2018;190:396-403.
Borst GR, De Jaeger K, Belderbos JS, Burgers SA, Lebesque JV. Pulmonary function changes after radiotherapy in non-small-cell lung cancer patients with long-term disease-free survival. Int J Radiat Oncol Biol Phys 2005;62:639-44.
Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al.
Overall survival with durvalumab after chemoradiotherapy in Stage III NSCLC. N Engl J Med 2018;379:2342-50.
Voong KR, Naidoo J. Radiation pneumonitis after definitive chemoradiation and durvalumab for non-small cell lung cancer. Lung Cancer 2020;150:249-51.
Hassanzadeh C, Sita T, Savoor R, Samson PP, Bradley J, Gentile M, et al.
Implications of pneumonitis after chemoradiation and durvalumab for locally advanced non-small cell lung cancer. J Thorac Dis 2020;12:6690-700.
[Figure 1], [Figure 2], [Figure 3]